S216: CLINICAL ACTIVITY OF CC-99282, A CEREBLON E3 LIGASE MODULATOR (CELMOD) AGENT, IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA (R/R NHL) – RESULTS FROM A PHASE 1, OPEN-LABEL STUDY
Authors: J.-M. Michot, J. C. Chavez, C Carpio, S. Ferrari, T. A. Feldman, D. Morillo, J. Kuruvilla, A. Pinto, V. Ribrag, E Bachy, T. J. Buchholz, S. Carrancio, W.-C. Chou, C. Guarinos, F. Wu, S. Li, P. Patah, M. Pourdehnad, L. Nastoupil
Journal: HemaSphere (2022)

Background: CC-99282 is a novel, oral small molecule CELMoD® agent that co-opts cereblon to induce targeted degradation of Ikaros/Aiolos, transcription factors critical for development of B-cell malignancies. Compared with immunomodulatory drugs (IMiD®) and other CELMoD agents, CC-99282 had similar immunostimulatory effects and 10- to 100-fold stronger antiproliferative and apoptotic activity in preclinical models of diffuse large B-cell lymphoma (DLBCL). Aims: To evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), and preliminary efficacy of CC-99282 in pts with R/R NHL. Methods: CC-99282-NHL-001 (NCT03930953) is a 2-part multicenter first-in-human study comprising dose escalation of CC-99282 monotherapy (part A) and expansion with or without combination partners (part B). Part A includes pts with R/R DLBCL or follicular lymphoma (FL) who had progressed after ≥2 lines of therapy, including IMiD/CELMoD agents and chimeric antigen receptor T-cell (CAR-T) therapy, and pts with R/R DLBCL who received ≥1 line of standard therapy and are unfit for transplant. Pts receive oral CC-99282 0.2, 0.4, 0.6, or 0.8 mg once daily on 3 intermittent dosing schedules of 28-day cycles, with ≥3 pts per dosing cohort. Results: As of Oct 6, 2021, 50 pts were treated in part A (38 DLBCL, 12 FL; median age 66y; 58% male); 17 pts (34%) were ongoing and 26 pts (52%) discontinued due to progressive disease. Grade 3/4 CC-99282–related adverse events were reported in 32 pts (64%); the most common were neutropenia (29 pts [58%]), thrombocytopenia (4 pts [8%]), and anemia (4 pts [8%]). Correlation analysis showed that grade 4 neutropenia in the first month was more strongly associated with number of prior lines of alkylating agent and anti-CD20 therapy than with CC-99282 dose level or schedule. Neutropenia was manageable with CC-99282 dose modifications and granulocyte colony–stimulating factors. All dose-limiting toxicities were hematologic. The maximal recommended doses for schedules of interest were 0.6 mg on 7/14 days and 0.4 mg on 14/28 days. For doses ≥0.4 mg on schedules of interest, the overall response rate was 42% (15/36 evaluable pts; 6 FL, 9 DLBCL), with complete responses in 6 pts and partial responses in 9 pts. Responders included pts previously treated with CAR-T therapy and/or IMiD/CELMoD agents. Responses were durable, with median durations of 239 days (range 48–587; median follow-up [mFUP] 247 days [range 21–690]) and 112 days (range 63–414; mFUP 121 days [range 22–464]) for 7/14- and 14/28-day schedules, respectively. CC-99282 was absorbed rapidly and had a prolonged terminal half-life (median ~50 hours at doses ≥0.4 mg), with considerable distribution into the peripheral compartment. Increase in plasma CC-99282 and degradation of Ikaros/Aiolos in peripheral T cells occurred in a dose-dependent manner, and maximum degradation (>90%) occurred by day 4 of treatment at doses ≥0.4 mg. Within 2 weeks of initiating CC-99282, peripheral T-cell subsets showed a significant shift toward a more activated phenotype (P<0.05). Analysis of mutant circulating tumor DNA levels showed rapid reductions that correlated with response to CC-99282, suggesting strong tumor cell–intrinsic activity. Summary/Conclusion: CC-99282 monotherapy showed a manageable safety profile and demonstrated promising efficacy in heavily pretreated pts with R/R NHL. PK and pharmacodynamic data were consistent with robust and rapid CC-99282 antitumor activity. This study is ongoing, with patients actively being enrolled in the monotherapy and CC-99282+rituximab combination expansion cohorts.